1. Field of the Invention
The present invention relates to methods of treating neuromuscular degenerative disorders. More specifically, the present invention relates to methods of treating neuromuscular degenerative disorders by reducing the activation of NADPH Oxidase 2 (NOX2) either directly, or indirectly by means of the microtubule cytoskeleton.
2. Description of the Related Art
Duchenne Muscular Dystrophy (DMD) is a devastating, fatal, X-linked degenerative muscle disease that affects approximately 1 in 3,500 male births. While it is unequivocal that the absence of dystrophin is the molecular cause of DMD (1), the latency of disease presentation and spectrum of disease severity (2, 3) suggests that dystrophin alone does not explain the downstream muscle weakness and wasting. For example, several genetic factors have been identified that contribute to the onset and pathogenic progression of the disease (2, 3).
In human patients with DMD as well as in the most widely used murine model of DMD (mdx mouse), mechanical stress dependent dysregulation of Ca2+ and reactive oxygen species (ROS) signaling has been identified as a critical factor in the dystrophic process (4-6). In response to membrane stressors (isometric and eccentric contraction, acute osmotic challenge, membrane deformation with suction etc.) mdx myofibers demonstrate an inability to maintain a low myoplasmic [Ca2+] compared to wild-type due in large part to increased sarcolemmal Ca2+ influx through mechano-sensitive Ca2+ channels (7-11). With the same perturbation, exuberant ROS production is also evident in mdx fibers leading to increased in Ca2+ signaling dysfunction through oxidation of Ca2+ channels (12, 13).
Membrane stress induces ROS production within the skeletal muscle transverse tubule (14) by activation of NADPH Oxidase 2 (NOX2) (15) through a mechano-transduction dependent pathway. In conjunction with NOX2 dependent ROS production in mdx muscle, ROS production has also been identified secondary to Ca2+ entry into the mitochondria (16, 17). Acting independently or synergistically with Ca2+ influx, mechanical stress induced ROS production has been proposed as a mechanism for the increase in susceptibility to muscle damage in mdx mice (4, 6, 18). Despite these recent advances in understanding the contribution of mechanical stress to muscle dysfunction in DMD, mechanistic detail for the mechano-transduction dependent activation of Ca2+ and ROS pathways is limited.
The microtubule cytoskeleton resists mechanical perturbation in cells and in doing so act as a mechano-transducer (19-22). Dystrophin has been shown to be a microtubule associated protein (23). Nox2 has been shown to be activated by mechano-transduction (5, 14, 15) through Rac-1 as the mechano-sensitive element interacting with microtubules (24-26). In the heart, the microtubule network is critical for mechano-transduction dependent activation of Ca2+ (27, 28) and NOX2 dependent ROS (27) signaling during diastolic stretch.
The prior art is deficient in means of treating muscular conditions, muscular dystrophies, as well as improving the function of normal muscle tissue. The present invention fulfills this longstanding need and desire in the art.